Exploring Kinetic Scenarios for Allosteric Transitions of Calmodulin through Coarse-Grained Simulations

Abstract

Although the two domains of Calmodulin (CaM) are topologically similar, they differ in structural flexibility, stability, and Calcium binding affinity. Our coarse-grained simulations of the open-closed conformational transitions in Calcium-free Calmodulin (CaM) suggest kinetic scenarios in which the transition mechanisms for the two domains are distinct as well. Both domains have the same qualitative thermodynamic mechanisms: a “low temperature” two-state mechanism in which the domain remains relatively structured throughout the transition, and a “high temperature” mechanism involving a partially folded, unstable intermediate in the transition landscape. Under the same simulation conditions, the N-terminal domain (nCaM) exhibits two-state behavior, while the C-terminal domain (cCaM) populates the partially folded intermediate. The simulated transition rate for cCaM is much smaller due to the transient unfolding and refolding along the transition route compared to the two-state transition rate for nCaM. Differences in transition rates for the Calcium-free open/closed transition could explain measured binding rates of Ca2+ for the different domains. For example, slower conformational kinetics caused by the partially folded intermediate may bias cCaM towards a conformational selection binding mechanism, while nCaM maintains induced fit binding under some range of calcium concentration. Here, we explore such binding scenarios qualitatively.